POS1413 PRECLINICAL EVIDENCE FOR THE GLUCOCORTICOID-SPARING POTENTIAL OF A DUAL TLR7/8 INHIBITOR IN AUTOIMMUNE DISEASES
Authors: A. Deshmukh, A. Pereira, N. Geraci, E. Tzvetkov, M. Przetak, M. Catalina, E. F. Morand, A. Bender, B. Vaidyanathan
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Toll-like receptor 7 (TLR7) and TLR8 are single-stranded RNA-sensing endosomal pattern recognition receptors that evolved to defend against viral infections, however their dysregulation and activation by endogenous ligands has been implicated in autoimmune diseases including lupus. While glucocorticoids (GC) are effective, they have many undesirable effects that limit their use. In addition, resistance to GC, which was recently shown to be imparted by TLR activation and Type I interferon (IFN), is a major challenge for the treatment of patients with autoimmune diseases including lupus. New treatment approaches that allow for the use of lower doses of GC would be highly beneficial. <h3>Objectives</h3> To evaluate the GC-sparing effects of a dual TLR7 and TLR8 inhibitor (TLR7/8i). <h3>Methods</h3> Human peripheral blood mononuclear cells (PBMC) from healthy donors were treated with TLR7/8i, dexamethasone, or both. Cytokine production was measured using an AlphaLISA immunoassay, gene expression was analyzed by NanoString and single-cell RNA sequencing, and effects on protein markers were evaluated by flow cytometry. In addition, the efficacy of combined TLR7/8i and dexamethasone treatment was evaluated in the MRL/<i>lpr</i> mouse model of lupus. <h3>Results</h3> Studies in human PBMCs revealed synergistic effects of TLR7/8i and GC on inflammatory cytokine production resulting in increased GC potency in the presence of TLR7/8i (Figure 1A), an effect that was most pronounced in myeloid cells, especially monocytes (Figure 1B). Gene expression analysis revealed that the combination of TLR7/8i plus GC substantially impacted myeloid cell clusters, particularly modules for IFN and GC response genes, as well as nuclear factor-kappa B-regulated cytokines. Treatment with TLR7/8i and GC <i>in vivo</i> was more efficacious then either agent alone, as evidenced by reduced proteinuria (Figure 1C) and improved survival. <h3>Conclusion</h3> These results demonstrate that TLR7/8 inhibition increases the potency of GC by alleviating TLR activation-dependent GC resistance in a cell type-specific manner. Our findings suggest a GC-sparing potential for TLR7/8i compounds and indicate that TLR7/8 inhibition may offer a new therapeutic strategy for the treatment of autoimmune diseases. The safety, efficacy and GC-sparing effect of the TLR7/8i enpatoran is being evaluated in patients with systemic and/or cutaneous lupus erythematosus in the randomized, double-blind, placebo-controlled Phase II WILLOW study (NCT05162586), which has a mandatory GC tapering schedule. <h3>Acknowledgements</h3> This study was sponsored by EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. Medical writing support was provided by Bioscript Group Ltd, Macclesfield, UK, and funded by Merck Healthcare KGaA, Darmstadt, Germany. <h3>Disclosure of Interests</h3> Ankita Deshmukh Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Albertina Pereira Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Nicholas Geraci Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Evgeni Tzvetkov Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Melinda Przetak Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Michelle Catalina Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Eric F. Morand Consultant of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Grant/research support from: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Andrew Bender Shareholder of: Merck KGaA, Darmstadt, Germany, Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Bharat Vaidyanathan Employee of: EMD Serono Research &amp; Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA.